Role of Annexin-II in GI cancers: interaction with gastrins/progastrins.

The role of the gastrin peptide hormones (G17, G34) and their precursors (progastrins, PG; gly-extended gastrin, G-gly), in gastrointestinal (GI) cancers has been extensively reviewed in recent years [W. Rengifo-Cam, P. Singh, Role of progastrins and gastrins and their receptors in GI and pancreatic cancers: targets for treatment, Curr. Pharm. Des. 10 (19) (2004) 2345-2358; M. Dufresne, C. Seva, D. Fourmy, Cholecystokinin and gastrin receptors, Physiol. Rev. 86 (3) (2006) 805-847; A. Ferrand, T.C. Wang, Gastrin and cancer: a review, Cancer Lett. 238 (1) (2006) 15-29]. A possible important role of progastrin peptides in colon carcinogenesis has become evident from experiments with transgenic mouse models [W. Rengifo-Cam, P. Singh, (2004); A. Ferrand, T.C. Wang, (2006)]. It is now known that growth stimulatory and co-carcinogenic effects of gastrin/PG peptides are mediated by both proliferative and anti-apoptotic effects of the peptides on target cells [H. Wu, G.N. Rao, B. Dai, P. Singh, Autocrine gastrins in colon cancer cells Up-regulate cytochrome c oxidase Vb and down-regulate efflux of cytochrome c and activation of caspase-3, J. Biol. Chem. 275 (42) (2000) 32491-32498; H. Wu, A. Owlia, P. Singh, Precursor peptide progastrin(1-80) reduces apoptosis of intestinal epithelial cells and upregulates cytochrome c oxidase Vb levels and synthesis of ATP, Am. J. Physiol. Gastrointest. Liver Physiol. 285 (6) (2003) G1097-G1110]. Several receptor subtypes have been described that mediate growth effects of gastrin peptides [W. Rengifo-Cam, P. Singh (2004); M. Dufresne, C. Seva, D. Fourmy, (2006)]. Recently, we identified Annexin II as a high affinity binding protein for gastrin/PG peptides [P. Singh, H. Wu, C. Clark, A. Owlia, Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells, Oncogene (2006), doi:10.1038/sj.onc.1209798]. Importantly, the expression of Annexin II was required for mediating growth stimulatory effects of gastrin and PG peptides on intestinal epithelial and colon cancer cells [P. Singh, H. Wu, C. Clark, A. Owlia, Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells, Oncogene (2006), doi:10.1038/sj.onc.1209798], suggesting that Annexin-II may represent the elusive novel receptor for gastrin/PG peptides. The importance of this finding in relation to the structure and function of Annexin-II, especially in GI cancers, is described below. Since this surprising finding represents a new front in our understanding of the mechanisms involved in mediating growth effects of gastrin/PG peptides in GI cancers, our current understanding of the role of Annexin-II in proliferation and metastasis of cancer cells is additionally reviewed.